Cocaine crosses the placenta and induces neurobehavioral abnormalities in offsprings of mothers ingesting this stimulant during pregnancy, thus suggesting that cocaine targets the developing brain. Cocaine competitively inhibits the removal of synaptic dopamine (DA) and other monoamines and thus increases synaptic concentrations of neurotransmitters which are known to influence the development and maturation of the CNS. It was therefore hypothesized that the increase in synaptic transmitter concentrations during CNS maturation results in cellular and neurochemical adaptive changes which lead to long term behavioral aberrations. In previously performed investigations, we demonstrated that prenatal exposure of rabbits to cocaine 1) reduced coupline of D1 DA receptors to Galphas protein in cortex and striatum, and 2) diminished evoked release of cortical DA. These effects were observed on postnatal days 10 to 100. It is proposed that the persistent functional changes in dopaminergic neurotransmission observed after prenatal cocaine are the consequences of desensitization of the D1 DA system that results from cocaine-induced insult to this neurotransmitter system during gestation. The proposed studies aim at defining the molecular mechanisms responsible for the apparent uncoupling of the D1 DA receptor transduction system and the functional consequences of this effect on DA neurotransmission. Specifically, experiments are designed to 1) explore the role of posttranslational modifications of Galphas and of D1 receptors in producing uncoupling of the D1 receptor system, 2) establish how early in development D1 receptors uncouple from Gs, 3) test whether the D1 receptor also uncouples from Galphaq which is linked to phosphatidylinositol hydrolysis, 4) test whether D1 receptor-Gs uncoupling results in desensitization of D1 receptor-mediated functions, and 5) test the specificity of the effects of prenatal cocaine treatment in terms of brain region, neurotransmitter system, and receptor subtype. Understanding the mechanism by which in utero cocaine impairs normal neurodevelopment and produces its long-term neurobehavioral abnormalities will ultimately enable us to design specific strategies to prevent or counter the consequences of cocaine abuse during pregnancy.